Aims <p>This study aimed to evaluate whether native cystic duct morphology and biliary anatomical variations assessed on MRCP are associated with the development of acute cholecystitis, beyond classical mechanisms of gallstone obstruction and infection.</p> Methods <p>A retrospective analysis was conducted on 112 patients who underwent MRCP between 2015 and 2024, including 82 with acute cholecystitis and 30 controls. Cystic duct tortuosity, configuration, orientation, confluence site and level, and cystic duct–common bile duct (CBD) angulation were systematically assessed. Group comparisons were performed, and independent predictors of acute cholecystitis were identified using multivariable logistic regression.</p> Results <p>Cystic duct tortuosity was significantly more frequent in the acute cholecystitis group (57.3% vs. 26.7%, <i>p</i> = 0.004). Narrow cystic duct–CBD angulation was also associated with acute cholecystitis (median 105° vs. 120°, <i>p</i> = 0.002), and angles ≤ 90° occurred exclusively in affected patients. Logistic regression identified tortuosity (OR = 10.42, <i>p</i> &lt; 0.001), narrow angulation (OR = 0.97 per degree, <i>p</i> = 0.032), and long-parallel linear configuration (OR = 7.96, <i>p</i> = 0.005) as independent risk factors, whereas posterior (OR = 0.26) and medial (OR = 0.20) confluence patterns appeared protective.</p> Conclusions <p>MRCP-based cystic duct morphology significantly influences the risk of acute cholecystitis. Tortuosity, narrow angulation, and long-parallel configurations increase susceptibility, while certain confluence patterns may be protective. These anatomical features may assist in preoperative risk stratification and anticipation of difficult cholecystectomy.</p>